Deazapurine derivatives; a new class of CRF1 specific ligands

ABSTRACT

Disclosed are compounds of the formula   &lt;IMAGE&gt;   wherein Ar represents an aryl or heteroaryl group; and R1, R2, R3, R4, and R5 represent organic or inorganic substituents, which compounds are highly selective partial agonists or antagonists at human CRF1 receptors and, thus, are useful in the diagnosis and treatment of treating stress related disorders such as post trumatic stress disorder (PTSD) as well as depression, headache and anxiety.

BACKGROUND OF THE INVENTION

This invention relates to novel substituted deazapurine derivativeswhich selectively bind to CRF receptors. More specifically, it relatesto pyrrolo[3,2-d]pyrimidin-4-amines, pyrrolo[3,2-b]pyridin-4-amines, andpyrrolo[3,2b]pyridin-4-amines, and their use as antagonists ofCorticotropin-Releasing Factor in the treatment of various diseasestates.

2. Description of the Related art

Corticotropin-releasing factor (CRF) antagonists are mentioned in U.S.Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinederivatives, respectively. The importance of CRF antagonists isdescribed in the literature, for example, as discussed in U.S. Pat. No.5,063,245, which is incorporated herein by reference in its entirety.CRF antagonists are considered effective in the treatment of a widerange of diseases including stress-related illnesses, such asstress-induced depression, anxiety, and headache. Other diseasesconsidered treatable with CRF antagonists are discussed in U.S. Pat. No.5,063,245 and Pharm. Rev., 43:425-473 (1991).

International application WO 9413676 A1 disclosespyrrolo[2,3-d]pyrimidines as having Corticotropin-Releasing Factorantagonist activity. J. Het. Chem. 9, 1077 (1972) describes thesynthesis of 9-Phenyl-pyrrolo[3,2d]pyrimidines.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact withCRF receptors.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. It further relates to the use of such compounds intreating stress related disorders such as post trumatic stress disorder(PTSD) as well as depression, headache and anxiety. Accordingly, a broadembodiment of the invention is directed to a compound of Formula I:##STR2## wherein Ar is phenyl, where the phenyl group is mono-, di-, ortrisubstituted with halogen, hydroxy, lower alkyl, or lower alkoxy, withthe proviso that at least one of the ortho positions of the phenyl groupis substituted; or

Ar is 2-, 3-, or 4-pyridyl, 2- or 3- thienyl, 4- or 5-pyrimidyl, each ofwhich is optionally mono-di-, or trisubstituted with halogen, hydroxy,lower alkyl, or lower alkoxy, with the proviso that at least one of theortho positions of the Ar substituent is substituted;

X is CH or nitrogen;

R₁ is lower alkyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or

R₁ and R₂ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --,

where n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR₆, where R₆ islower alkyl, and m is 0, 1 or 2;

R₃ and R₄ are the same or different and represent

hydrogen or lower alkyl;

phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, 4-, or5-pyrimidyl, each of which is optionally mono- or disubstituted withhalogen, hydroxy, lower alkyl, or lower alkoxy;

phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyllower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl;

cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where thecycloalkyl portion has 3-8 carbon atoms;

2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted withlower alkyl with the proviso that not both R₃ and R₄ are hydrogen; or

R₃ and R₄ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --

where n is 2, or 3,

A is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ islower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2-or 3-thienyl or 2-, 4-, or5-pyrimidyl, phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2-or3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl; and

m is 1, 2 or 3; and

R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.

These compounds, i.e., substituted deazapurine derivatives, are highlyselective partial agonists or antagonists at CRF receptors and areuseful in the diagnosis and treatment of stress related disorders suchas post trumatic stress disorder (PTSD) as well as depression andanxiety.

Thus, the invention provides compounds, including pharmaceuticallyacceptable salts of the compounds of formula I, and pharmaceuticalcompositions for use in treating disease states associated withCorticotropin-releasing factor. The invention further provides methodsincluding animal models relevant to the evaluation of the interaction ofthe compounds of the invention with CRF receptors. This interactionresults in the pharmacological activities of these compounds.

DETAILED DESCRIPTION OF THE INVENTION

In this document, all temperatures will be stated in degrees Celsius.All amounts, ratios, concentrations, proportions and the like will bestated in weight units, unless otherwise stated, except for ratios ofsolvents, which are in volume units.

In addition to compounds of general formula I described above, theinvention encompasses compounds of general formula IA: ##STR3## whereinAr is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3- thienyl, 4- or 5-pyrimidyl,each of which is mono-, di-, or trisubstituted with halogen, hydroxy,lower alkyl, or lower alkoxy, with the proviso that at least one of theortho positions of the Ar substituent is substituted;

X is CH or nitrogen;

R₁ is lower alkyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or

R₁ and R₂ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --,

where n is 2, 3 or 4, A is methylene, oxygen, sulfur or NR₆, where R₆ islower alkyl, and

m is 0, 1 or 2;

R₃ and R₄ are the same or different and represent

hydrogen or lower alkyl; phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl,or 2-, 4-, or 5-pyrimidyl, each of which is mono- or disubstituted withhalogen, hydroxy, lower alkyl, or lower alkoxy;

phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyllower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl;

cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where thecycloalkyl portion has 3-8 carbon atoms;

2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted withlower alkyl with the proviso that not both R₃ and R₄ are hydrogen; or

R₃ and R4 taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --

where n is 2, or 3,

A is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ islower alkyl, phenyl, 2-, 3-, or 4-pyridyl, 2-or 3-thienyl or 2-, 4-, or5-pyrimidyl, phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2-or3-thienyl lower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl, and

m is 1, 2 or 3; and

R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.

In the compounds of the invention, preferred NR₃ R₄ groups include thefollowing: ##STR4##

Preferred compounds of formula I are those where R₁ is methyl, ethyl orpropyl or isopropyl; R₂ is lower alkyl, halogen, or thio lower alkyl; R₅is lower alkyl or halogen; and R₇, R₈, and R₉ represent methyl, ethyl,propyl or isopropyl.

The invention provides compounds of formula II ##STR5## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and

R₃ represents lower alkyl, or cycloalkyl lower alkyl.

Preferred compounds of formula II are those where R₁ is methyl, ethyl orpropyl or isopropyl; and R₇, R₈, and R₉ represent methyl, ethyl, propylor isopropyl. Particularly preferred compounds of formula II are thosewhere R₁ is methyl, and R₇, R₈, and R₉ represent methyl.

The invention provides compounds of formula III ##STR6## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and

R₃ represents lower alkyl, or cycloalkyl lower alkyl; and

R₅ is lower alkyl, halogen, or thio lower alkyl.

Preferred compounds of formula III are those where R₁ is methyl, ethylor propyl or isopropyl; R₅ is halogen or thio lower alkyl; and R₇, R₈,and R₉ represent methyl, ethyl, propyl or isopropyl. Particularlypreferred compounds of formula III are those where R₁ is methyl; R₅ ishalogen, thiomethyl; and R₇, R₈, and R₉ represent methyl, ethyl, propylor isopropyl.

The invention provides compounds of formula IV ##STR7## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and

R₃ represents lower alkyl, or cycloalkyl lower alkyl; and

R₅ is lower alkyl, halogen, or thio lower alkyl.

Preferred compounds of formula IV are those where R₁ is methyl, ethyl orpropyl or isopropyl; R₅ is halogen or thio lower alkyl; and R₇, R₈, andR₉ represent methyl, ethyl, propyl or isopropyl. Particularly preferredcompounds of formula IV are those where R₁ is methyl; R₅ is halogen,thiomethyl; and R₇, R₈, and R₉ represent methyl, ethyl, propyl orisopropyl.

The invention provides compounds of formula V ##STR8## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and

R₃ represents lower alkyl, or cycloalkyl lower alkyl.

Preferred compounds of formula V are those where R₁ is methyl, ethyl orpropyl or isopropyl; and R₇, R₈, and R₉ represent methyl, ethyl, propylor isopropyl. Particularly preferred compounds of formula V are thosewhere R₁ is methyl, and R₇, R₈, and R₉ represent methyl.

The invention provides compounds of formula VI ##STR9## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and _(R) ₃ represents loweralkyl, or cycloalkyl lower alkyl; and _(R) ₅ is lower alkyl, halogen, orthio lower alkyl.

Preferred compounds of formula VI are those where R₁ is methyl, ethyl orpropyl or isopropyl; R₅ is halogen or thio lower alkyl; and R₇, R₈, andR₉ represent methyl, ethyl, propyl or isopropyl. Particularly preferredcompounds of formula VI are those where R₁ is methyl; R₅ is halogen,thiomethyl; and R₇, R₈, and R₉ represent methyl, ethyl, propyl orisopropyl.

The invention provides compounds of formula VII: ##STR10## wherein R₄represents hydrogen or lower alkyl;

R₁, R₇, R₈, and R₉ represent lower alkyl; and _(R) ₃ represents loweralkyl, or cycloalkyl lower alkyl; and

R₅ is lower alkyl, halogen, or thio lower alkyl.

Preferred compounds of formula VII are those where R₁ is methyl, ethylor propyl or isopropyl; R₅ is halogen or thio lower alkyl; and R₇, R₈,and R₉ represent methyl, ethyl, propyl or isopropyl. Particularlypreferred compounds of formula VII are those where R₁ is methyl; R₅ ishalogen, thiomethyl; and R₇, R₈, and R₉ represent methyl, ethyl, propylor isopropyl.

In each of formulas II to VII, NR3R₄ optionally represents --(CH₂)_(n)--A--(CH₂)_(m) -- where m, n, and A are as defined above for formula I.

The invention also provides compounds of formula VIII: ##STR11## whereinAr is phenyl, 2-, 3-, or 4-pyridyl, 2- or 3- thienyl, 4- or 5-pyrimidyl,each of which is mono-, di-, or trisubstituted with halogen, hydroxy,lower alkyl, or lower alkoxy, with the proviso that at least one of theortho positions of the Ar substituent is substituted;

X is CH or nitrogen;

R₁ is lower alkyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or

R₃ and R₄ are the same or different and represent

hydrogen or lower alkyl;

phenyl, 2-, 3-, or 4-pyridyl, 2-, or 3-thienyl, or 2-, 4-, or5-pyrimidyl, each of which is mono- or disubstituted with halogen,hydroxy, lower alkyl, or lower alkoxy;

phenyl lower alkyl, 2-, 3-, or 4-pyridyl lower alkyl, 2- or 3-thienyllower alkyl, or 2-, 4-, or 5-pyrimidyl lower alkyl;

cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where thecycloalkyl portion has 3-8 carbon atoms;

2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted withlower alkyl with the proviso that not both R₃ and R₄ are hydrogen;

R₃ and R₄ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --

where n is 2, or 3,

A is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ islower alkyl; and

m is 1, 2 or 3; and

R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.

In addition, the invention provides compounds of formula IX: ##STR12##wherein Ar is phenyl mono-, di-, or trisubstituted with halogen,hydroxy, lower alkyl, or lower alkoxy, with the proviso that at leastone of the ortho positions of the Ar substituent is substituted;

X is nitrogen;

R₁ is lower alkyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or

R₃ and R₄ are the same or different and represent

hydrogen or lower alkyl;

cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where thecycloalkyl portion has 3-8 carbon atoms;

2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted withlower alkyl with the proviso that not both R3 and R4 are hydrogen; or

R₃ and R₄ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --

where n is 2, or 3,

A is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ islower alkyl; and

m is 1, 2 or 3;

R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.

Further, the invention provides compounds of formula X: ##STR13##wherein Ar is phenyl mono-, di-, or trisubstituted with halogen,hydroxy, lower alkyl, or lower alkoxy, with the proviso that at leastone of the ortho positions of the Ar substituent is substituted;

R₁ is lower alkyl;

R₂ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy; or

R₃ and R₄ are the same or different and represent

hydrogen or lower alkyl;

cycloalkyl having 3-8 carbon atoms or cycloalkyl lower alkyl where thecycloalkyl portion has 3-8 carbon atoms;

2-hydroxyethyl or 3-hydroxypropyl optionally mono or disubstituted withlower alkyl with the proviso that not both R3 and R4 are hydrogen; or

R₃ and R₄ taken together represent --(CH₂)_(n) --A--(CH₂)_(m) --

where n is 2, or 3,

A is methylene, 1,2 phenylene, oxygen, sulfur or NR₆, wherein R₆ islower alkyl; and

m is 1, 2 or 3;

R₅ is hydrogen, halogen, lower alkyl, lower alkoxy, or thioalkoxy.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts. Non-toxic pharmaceuticallyacceptable salts include salts of acids such as hydrochloric,phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluene sulfonic,hydroiodic, acetic and the like. Those skilled in the art will recognizea wide variety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

By aryl or "At" is meant an aromatic carbocyclic group having a singlering (e.g., phenyl), multiple rings (e.g., biphenyl), or multiplecondensed tings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy.

By aryl or "Ar" is also meant heteroaryl groups where heteroaryl isdefined as 5, 6, or 7 membered aromatic ring systems having at least onehetero atom selected from the group consisting of nitrogen, oxygen andsulfur. Examples of heteroaryl groups are pyridyl, pyrimidinyl,pyrrolyl, pyrazolyl, pyrazinyl, pyridazinyl, oxazolyl, furanyl,quinolinyl, isoquinolinyl, thiazolyl, and thienyl, which can optionallybe substituted with, e.g., halogen, lower alkyl, lower alkoxy, loweralkylthio, trifluoromethyl, lower acyloxy, aryl, heteroaryl, andhydroxy.

By alkyl and lower alkyl is meant straight and branched chain alkylgroups having from 1-6 carbon atoms. Specific examples of alkyl groupsare methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl,sec-butyl, neopentyl and n-pentyl.

By lower alkoxy and alkoxy is meant straight and branched chain alkoxygroups having from 1-6 carbon atoms.

By thioalkoxy is meant a straight or branched chain alkoxy group havingfrom 1-6 carbon atoms and a terminal sulfhydryl, i.e., --SH, moiety.

By thio lower alkyl as used herein is meant a lower alkyl group having aterminal sulfhydryl, i.e., --SH, group.

By halogen is meant fluorine, chlorine, bromine and iodine.

Representative examples of pyrrolo[3,2-d]pyrimidines according to theinvention are shown in Table 1 below.

                  TABLE 1.sup.1                                                   ______________________________________                                         ##STR14##                     1                                               ##STR15##                     2                                               ##STR16##                     3                                               ##STR17##                     4                                               ##STR18##                     5                                               ##STR19##                     6                                               ##STR20##                     7                                               ##STR21##                     8                                               ##STR22##                     9                                               ##STR23##                     10                                              ##STR24##                     11                                              ##STR25##                     12                                              ##STR26##                     13                                              ##STR27##                     14                                              ##STR28##                     15                                              ##STR29##                     16                                              ##STR30##                     17                                              ##STR31##                     18                                              ##STR32##                     19                                              ##STR33##                     20                                              ##STR34##                     21                                             ______________________________________                                         .sup.1 The number below each compound is its compound number.            

The pharmaceutical utility of compounds of this invention is indicatedby the following assay for CRF receptor activity.

Assay for CRF receptor binding activity

CRF receptor binding was performed using a modified version of the assaydescribed by Grigoriadis and De Souza (Biochemical, Pharmacological, andAutoradiographic Methods to Study Corticotropin-Releasing FactorReceptors. Methods in Neurosciences, Vol. 5, 1991). Membrane pelletscontaining CRF receptors were resuspended in 50 mM Tris buffer pH 7.7containing 10 mM MgCl₂ and 2 mM EGTA and centrifuged for 10 minutes at48000 g. Membranes were washed again and brought to a finalconcentration of 1500 μg/ml in binding buffer (Tris buffer above with0.1% BSA, 0.15 mM bacitracin and 0.01 mg/ml aprotinin.). For the bindingassay, 100 μl of the membrane preparation was added to 96 well microtubeplates containing 100 μl of ¹²⁵ I-CRF (SA 2200 Ci/mmol, finalconcentration of 100 pM) and 50 μl of drug. Binding was carried out atroom temperature for 2 hours. Plates were then harvested on a Brandel 96well cell harvester and filters were counted for gamma emissions on aWallac 1205 Betaplate liquid scintillation counter. Non specific bindingwas defined by 1 μM cold CRF. IC₅₀ values were calculated with thenon-linear curve fitting program RS/1 (BBN Software Products Corp.,Cambridge, Mass.). The binding characteristics for examples from thispatent are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                        Compound Number.sup.2                                                                          IC.sub.50 (uM)                                               ______________________________________                                        1                0.110                                                        5                0.500                                                        ______________________________________                                         .sup.2 Compound numbers relate to compounds shown above in Table 1.      

Compounds 1 and 5 are particularly preferred embodiments of the presentinvention because of their potency in binding to CRF receptors.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

A representative illustration of methods suitable for the preparation ofcompounds of the present invention is shown in Schemes I and II. Thosehaving skill in the art will recognize that the starring materials maybe varied and additional steps employed to produce compounds encompassedby the present invention. ##STR35##

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE IA ##STR36##

To a stirred mixture of sodium methoxide (2.78 g, 51 mmol) and ethylformate (4.0 g, 54 mmol) in 100 mL of benzene was added 2,4,6trimethylphenylacetonitrile (8.0 g, 50 mmol) over 5 min. After stirringfor an additional hour it was treated with water (100 mL) and the layerswere separated. The aqueous layer was separated and acidified with 10%HCl and extracted with ethyl acetate. After drying the solvent wasremoved in vacuo to afford a-formyl-2,4,6-trimethylphenylacetonitrile ascolorless crystals melting at 120°-122° C.

EXAMPLE IB ##STR37##

A mixture of a-formyl-2,4,6 trimethylphenylacetonitrile (4.5 g, 24 mmol)and sarcosine ethyl ester hydrochloride (3.7 g, 24 mmol) in 100 mL ofbenzene was refluxed in a Dean-Stark apparatus for 16 h. The solvent wasremoved in vacuo to affordN-Methyl-N-[2-(2,4,6-trimethylphenyl)-2-cyanovinyl]-glycine ethyl esteras a pale yellow oil.

EXAMPLE IC ##STR38##

A solution ofN-Methyl-N-[2-(2,4,6-trimethylphenyl)-2-cyanovinyl]-glycine ethyl ester(6.8 g, 24 mmol) in 0.28M ethanolic sodium ethoxide (100 mL) was heatedat 70° C. for 6 h. The reaction was cooled and evaporated in vacuo. Theresidue was treated with water and neutralized with acetic acid and theproduct was extracted with ethyl acetate. After drying the solvent wasremoved in vacuo to afford3-Amino-2-ethoxycarbonyl-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrroleas a yellow oil.

EXAMPLE ID ##STR39##

A solution of3-Amino-2-ethoxycarbonyl-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole(2.0 g, 7 mmol) in 20 mL of formamide was heated at 140° C. for 12 h.After cooling the mixture was poured into water and the resulting solidwas collected and washed with more water and dried to afford5-Methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol as atan solid melting at 230°-232° C.

EXAMPLE IE ##STR40##

A mixture of5-Methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (100mg) and phosphorous oxychloride (0.5 mL) was heated at reflux for 3hours. Excess reagent was removed in vacuo and the residual 4-chlorocompound was treated with N-propylcyclopropylmethylamine (100 mg) andtriethylamine (100 mg) in xylene (2 mL) and the mixture was refluxed for8 hours.

After diluting the reaction mixture with ethyl acetate and washing withdilute bicarbonate solution, the organic layer was dried and the solventremoved in vacuo. The residue was chromatagraphed on silica gel toaffordN-cyclopropylmethyl-N-propyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 1) as an oil. The HCl salt from ethylacetate/HCl melted at 205°-207° C.

EXAMPLE II

The following compounds are prepared essentially according to theprocedures described in Examples IA-E above.

a)N,N-Dipropyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 2) melting at 116°-118° C.

b)N,N-Diethyl-5-methyl-7-(2,4,6-trimethylphenyl)5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 3).

c)N,N-Dimethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 4).

d)N-Butyl-N-Ethyl-5-methyl-7(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 5) melting at 126°-128° C.

e)N-(2-Hydroxyethyl)-N-Ethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 6).

f)4-(1-Homopiperidinyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidine(Compound7) melting at 140°-142° C.

g)N-(1-Ethylpropyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine(Compound 8).

h)N-(1-Hydroxymethylpropyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine(Compound 9) melting at 118°-120° C.

i)N,N-Dipropyl-5,6-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 10).

j)N-(1-Hydroxymethylpropyl)-5,6-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine (Compound 11).

k)N-(1-Hydroxymethylpropyl)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine (Compound 12).

l) N,N-Dipropyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 13).

m)N-Cyclopropylmethyl-N-propyl-6-chloro-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo [3,2-d]pyrimidin-4-amine (Compound 14).

n)N-Cyclopropylmethyl-N-propyl-2-chloro-5methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 15).

o)N-Cyclopropylmethyl-N-propyl-6-bromo-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 16).

p)N-Cyclopropylmethyl-N-propyl-6-thiomethyl-5-methyl-7-(2,4,6-trimethylphenyl)5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 17).

q)N-Cyclopropylmethyl-N-propyl-2-thiomethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine (Compound 18).

r)N-Cyclopropylmethyl-N-propyl-2-chloro-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-bpyridin-4-amine (Compound 19).

s)N-Cyclopropylmethyl-N-propyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-bpyridin-4-amine(Compound 20).

t)N-(Hydroxymethylpropyl)-5methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2bpyridin-4-amine(Compound 21).

u)N-Cyclopropylmethyl-N-propyl-5-amino-9-(2,4,6-trimethylphenyl)-1,2-dihydro-3H-pyrimido[5,4-e]pyrrolizine (Compound 22).

v)N-(1-Hydroxymethylpropyl)-5-amino-9-(2,4,6-trimethylphenyl)-1,2-dihydro-3H-pyrimido[5,4e]pyrrolizine (Compound 23).

w)N-Cyclopropylmethyl-N-propyl-5-amino-7-methyl-9-(2,4,6-trimethylphenyl)-1,2-dihydro-3H-pyrimido[5,4-e]pyrrolizine (Compound 24).

x)N-Cyclopropylmethyl-N-propyl-5-amino-9-(2,4-dichlorophenyl)-1,2-dihydro-3H-pyrimido[5,4-e]pyrrolizine (Compound 25).

y)N,N-Dipropyl-5-methyl-7-(2,4-dichlorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(Compound 26).

z)N-Cyclopropylmethyl-N-propyl-5-amino-9-(2,4,6-trimethylphenyl)-1,2-dihydro-3H-pyrido[2,3-e]pyrrolizine (Compound 27).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR41## or thepharmaceutically acceptable salts thereof wherein: R_(a), R_(b), andR_(c) independently represent hydrogen, halogen, hydroxy, lower alkyl,or lower alkoxy, with the proviso that at least one of R_(a), R_(b), orR_(c) is in an ortho position of the phenyl group to which they areattached;R₁ is lower alkyl; R₂ is hydrogen, halogen, lower alkyl, loweralkoxy, or thioalkyl; R₃ and R₄ are the same or different and representhydrogen, lower alkyl, cycloalkyl having 3-8 carbon atoms, or cycloalkyllower alkyl where the cycloalkyl portion has 3-8 carbon atoms, orhydroxy lower alkyl with the proviso that not both R₃ and R₄ arehydrogen; or R₃ and R₄ taken together represent --(CH₂)_(n) --CH₂--(CH₂)_(m) --where n is 2 or 3, and m is 1, 2 or 3; and R₅ is hydrogen,halogen, lower alkyl, lower alkoxy, or thioalkyl.
 2. A compoundaccording to claim 1, wherein R₁ is methyl.
 3. A compound according toclaim 1, wherein R₂ is methyl, thiomethyl, or a bromine or chlorineatom, and R₁ is methyl.
 4. A compound according to claim 1, wherein R₁and R₅ are methyl.
 5. A compound according to claim 1, wherein R_(a),R_(b), and R_(c) each represent methyl.
 6. A compound according to claim5, wherein R_(a), R_(b), and R_(c) are in the ortho, ortho, and parapositions, respectively, of the phenyl ring.
 7. A compound according toclaim 1, wherein NR₃ R₄ is a hydroxy lower alkyl group.
 8. A compoundaccording to claim 7, wherein the hydroxy lower alkyl group is1-hydroxymethylpropyl or 2-hydroxyethyl.
 9. A compound according toclaim 1, where NR₃ R₄ representsN-Cyclopropylmethyl-N-propyl;N,N-Dipropyl; N,N-Diethyl; N,N-Dimethyl; N-Butyl-N-ethyl;N-(2-Hydroxyethyl)-N-ethyl; Homopiperidinyl; N-(1-Ethylpropyl);N-(1-Hydroxymethylpropyl); or N-Cyclopropylmethyl-N-propyl.
 10. Acompound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.11. A compound according to claim 1 which isN,N-Dipropyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.12. A compound according to claim 1 which isN,N-Diethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.13. A compound according to claim 1 which isN,N-Dimethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.14. A compound according to claim 1 which isN-Butyl-N-ethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo]3,2-d]pyrimidin-4-amine.15. A compound according to claim 1 which isN-(2-Hydroxyethyl)-N-ethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.16. A compound according to claim 1 which is4-(1-Homopiperidinyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidine.17. A compound according to claim 1 which isN-(1-Ethylpropyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.18. A compound according to claim 1 which isN-(1-Hydroxymethylpropyl)-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.19. A compound according to claim 1 which isN,N-Dipropyl-5,6-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.20. A compound according to claim 1 which isN-(1-Hydroxymethylpropyl)-5,6-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.21. A compound according to claim 1 which isN-(1-Hydroxymethylpropyl)-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.22. A compound according to claim 1 which isN,N-Dipropyl-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2d]pyrimidin-4-amine.23. A compound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-6-chloro-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.24. A compound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-2-chloro-5methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.25. A compound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-6-bromo-5methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.26. A compound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-6-thiomethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.27. A compound according to claim 1 which isN-Cyclopropylmethyl-N-propyl-2-thiomethyl-5-methyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.28. A compound according to claim 1 which isN,N-Dipropyl-5-methyl-7-(2,4-dichlorophenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.